Benzamidine derivatives their preparation and their use as...

C - Chemistry – Metallurgy – 07 – D

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C07D 213/69 (2006.01) A61K 31/155 (2006.01) A61K 31/16 (2006.01) A61K 31/44 (2006.01) A61K 31/495 (2006.01) A61K 31/53 (2006.01) A61K 31/535 (2006.01) C07C 257/18 (2006.01) C07C 275/42 (2006.01) C07D 213/74 (2006.01) C07D 213/79 (2006.01) C07D 213/81 (2006.01) C07D 213/82 (2006.01) C07D 239/52 (2006.01) C07D 241/18 (2006.01) C07D 251/12 (2006.01) C07D 401/04 (2006.01) C07D 401/12 (2006.01) C07D 401/14 (2006.01) C07D 403/12 (2006.01) C07D 521/00 (2006.01)

Patent

CA 2214685

This invention is directed to benzamidine derivatives which are useful as anti-coagulants. This invention is also directed to pharmaceutical compositions containing the compounds of the invention, and methods of using the compounds to treat disease-states characterized by thrombotic activity. Accordingly, in one aspect, this invention provides compounds selected from the group consisting of formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII), wherein: A is -C(R11)= or -N=; Z1 and Z2 are independently -O-, -N(R8)-, -S-, or -OCH2-; R1 and R3 are independently hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, -N(R8)R9, -C(O)OR8, -C(O)N(R8)CH2C(O)N(R8)R9, - N(R8)C(O)N(R8)R9, -N(R8)C(O)R8, -N(R8)S(O)2R12, or -N(R8)C(O)N(R8)CH2C(O)N(R8)R9; R2 is hydrogen; halo; alkyl; haloalkoxy; -OR8; -C(O)OR8; -C(O)N(R8)R9; -N(R8)R9; -C(O)N(R8)(CH2)m C(O)OR8 (where m is 0 to 3); -N(R8)(CH2)n C(O)OR8 (where n is 1 to 3); -N((CH2)n N(R1)R9)(CH2)n C(O)OR8 (where each n is 1 to 3); -O(CH2)n C(O)N(R8)R9 (where n is 1 to 3); -O(CH2)p C(O)OR8 (where p is 1 to 6); -N(R8)(CH2)n C(O)N(R8)(CH2)n C(O)OR8 (where each n is independently 1 to 3); morpholin-4-yl; 3-tetrahydrofuranoxyl; etc.; R4 and R7 are independently hydrogen, halo, alkyl, nitro, -OR8, -C(O)OR8, -C(O)N(R8)R9, -N(R8)R9, -N(H)C(O)R8, or -N(H)S(O)2R12; R5 is -C(NH)NH2, -C(NH)N(H)OR8, - C(NH)N(H)C(O)OR12, -C(NH)N(H)S(O)2R12, -C(NH)N(H)C(O)N(R8)R9, or -C(NH)N(H)C(O)R8; R6 is halo, alkyl, haloalkyl, haloalkoxy, nitro, amino, ureido, guanidino, -OR8, -C(NH)NH2, -C(NH)NHOH, -C(O)R10, -(CH2)m C(O)N(R8)R9 (where m is 0 to 3), - CH(OH)C(O)N(R8)R9, -(CH2)m N(R8)R9 (where m is 0 to 3), -(CH2)m C(O)0R8 (where m is 0 to 3), -N(H)C(O)R8, (1,2)- tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl); each R8 and R9 is independently hydrogen alkyl, aryl, or aralkyl; R10 is hydrogen, alkyl, aryl, aralkyl, 1-pyrrolidinyl, 4- morpolinyl, 4-piperazinyl, 4-(N-methyl)piperazinyl, or piperidin-1-yl; R11 is hydrogen, alkyl or halo; and R12 is alkyl, aryl or aralkyl; or a pharmaceutically acceptable salt thereof.

La présente invention concerne des dérivés de benzamidine pouvant être utilisés en tant qu'anticoagulants. Cette invention concerne également des compositions pharmaceutiques contenant des composés décrits dans cette même invention, ainsi que des procédés d'utilisation de ces composés afin de traiter des états maladifs qui se caractérisent par une activité thrombotique. Ainsi, sous l'un de ses aspects, cette invention propose des composés choisis dans le groupe se composant des formules suivantes (I), (II), (III), (IV), (V), (VI), (VII), et (VIII), où A est -C(R<11>)= ou -N=; Z<1> et Z<2> sont indépendamment -O-, -N(R<8>)-, -S- ou -OCH2-; R<1> et R<3> sont indépendamment hydrogène, halo, alkyle, haloalkyle, alcoxy, haloalcoxy, nitro, -N(R<8>)R<9>, -C(O)OR<8>, -C(O)N(R<8>)R<9>, -C(O)N(R<8>)CH2C(O)N(R<8>)R<9>, -N(R<8>)C(O)N(R<8>)R<9>, -N(R<8>)C(O)R<8>, -N(R<8>)S(O)2R<12> ou -N(R<8>)C(O)N(R<8>)CH2C(O)N(R<8>)R<9>; R<2> est hydrogène, halo, alkyle, haloalcoxy, -OR<8>, -C(O)OR<8>, -C(O)N(R<8>)R<9>, -N(R<8>)R<9>, -C(O)N(R<8>)(CH2)mC(O)OR<8> (m variant entre 0 et 3), -N(R<8>)(CH2)nC(O)OR<8> (n variant entre 1 et 3), -N((CH2)nN(R<8>)R<9>)(CH2)nC(O)OR<8> (chaque n variant entre 1 et 3), -O(CH2)nC(O)N(R<8>)R<9> (n variant entre 1 et 3), -O(CH2)pC(O)OR<8> (p variant entre 1 et 6), -N(R<8>)(CH2)nC(O)N(R<8>)(CH2)nC(O)OR<8> (chaque n variant indépendamment entre 1 et 3), morpholin-4-yle, 3-tétrahydrofuranoxyle, etc.; R<4> et R<7> sont indépendamment hydrogène, halo, alkyle, nitro, -OR<8>, -C(O)OR<8>, -C(O)N(R<8>)R<9>, -N(R<8>)R<9>, -N(H)C(O)R<8> ou -N(H)S(O)2R<12>; R<5> est -C(NH)NH2, -C(NH)N(H)OR<8>, -C(NH)N(H)C(O)OR<12>; -C(NH)N(H)S(O)2R<12>, -C(NH)N(H)C(O)N(R<8>)R<9> ou -C(NH)N(H)C(O)R<8>; R<6> est halo, alkyle, haloalkyle, haloalcoxy, nitro, amino, uréido, guanidino, -OR<8>, -C(NH)NH2, -C(NH)NHOH, -C(O)R<10>, -(CH2)mC(O)N(R<8>)R<9> (m variant entre 0 et 3), -CH(OH)C(O)N(R<8>)R<9>, -(CH2)mN(R<8>)R<9> (m variant entre 0 et 3), -(CH2)mC(O)OR<8> (m variant entre 0 et 3), -N(H)C(O)R<8>, (1,2)-tétrahydropyrimidinyle (éventuellement substitué par un alkyle), (1,2)-imidazolyle (éventuellement substitué par un alkyle) ou (1,2)-imidazolinyle (éventuellement substitué par un alkyle); R<8> et R<9> sont chacun indépendamment hydrogène, alkyle, aryle ou aralkyle; R<10> est hydrogène, alkyle, aryle, aralkyle, 1-pyrrolidinyle, 4-morpolinyle, 4-pipérazinyle, 4-(N-méthyl)pipérazinyle ou pipéridine-1-yle; R<11> est hydrogène, alkyle ou halo et R<12> est alkyle, aryle ou aralkyle. Cette invention concerne enfin tout sel desdits composés acceptable sur le plan pharmaceutique.

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